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Fully-functionalised probes for chemical proteomics

用于化学蛋白质组学的全功能化探针

基本信息

批准号：
2594486
负责人：
金额：
--
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2594486
关键词：
Fully functionalised probes chemical proteomics

项目摘要

Identifying and exploring new biologically-relevant chemical space is a major challenge that is central to both chemical biology and medicinal chemistry. Readily-available chemical probes can dramatically influence the biomedical science that is investigated experimentally. Yet, identifying new biologically-relevant chemical space is hampered by the uneven exploration of both biology and chemistry. Biologists favourite proteins are largely unchanged for more than 20 years despite a lack of evidence supporting their particular relevance to disease. Moreover, bioactive small molecule discovery continues to be underpinned by a remarkably narrow reaction toolkit that limits the scaffold diversity of explored chemical space. How, then, can new connections between phenotypes, target proteins and bioactive chemotypes be established to further our understanding of biology and, ultimately, to treat disease?This project will focus on the development of approaches that enable the one-pot synthesis of diverse small molecule probes that are already fully-functionalised for chemical biology studies. The resulting probes will thus reside in novel chemical space; will be armed with diverse electrophilic warheads; and will already be functionalised with clickable alkyne tags. The student will demonstrate that these diverse chemical probes can be harnessed to unlock new regions of biologically-relevant chemical space, and may reveal insights into the molecular basis of cell biology mechanisms. These tools may unlock new therapeutic strategies for the treatment of disease.The specific objectives are:1. To identify viable substrate sets for one-pot chemical probe synthesis;2. To prepare a diverse set of fully-functionalised probes using one-pot connective chemistry3. To assess the probe set in model biological systems

识别和探索新的生物相关化学空间是化学生物学和药物化学的主要挑战。现成的化学探针可以极大地影响实验研究的生物医学科学。然而，识别新的生物相关化学空间受到生物学和化学探索不平衡的阻碍。生物学家最喜欢的蛋白质在20多年里基本上没有变化，尽管缺乏证据支持它们与疾病的特殊相关性。此外，生物活性小分子的发现继续受到非常狭窄的反应工具包的支持，这限制了所探索的化学空间的支架多样性。那么，如何在表型、靶蛋白和生物活性化学型之间建立新的联系，以进一步理解生物学，并最终治疗疾病？该项目将专注于开发能够一锅合成已经完全功能化用于化学生物学研究的各种小分子探针的方法。由此产生的探针将驻留在新的化学空间中;将配备各种亲电子弹头;并且已经用可点击的炔标记进行功能化。学生将证明，这些不同的化学探针可以用来解锁生物相关化学空间的新区域，并可能揭示细胞生物学机制的分子基础。这些工具可能为疾病的治疗开启新的治疗策略。鉴定用于一锅法化学探针合成的可行底物组;2.使用一锅连接化学制备一组不同的全功能化探针3。评估模型生物系统中的探针组